Browsing by Subject "resistance"
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Item Daily Situational Brief, January 27, 2015(MESH Coalition, 1/27/2015) MESH CoalitionItem eIF3a Regulation of NHEJ Repair Protein Synthesis and Cellular Response to Ionizing Radiation(Frontiers, 2020-08-19) Tumia, Rima; Wang, Chao J.; Dong, Tianhan; Ma, Shijie; Beebe, Jenny; Chen, Juan; Dong, Zizheng; Liu, Jing-Yuan; Zhang, Jian-Ting; Pharmacology and Toxicology, School of MedicineTranslation initiation in protein synthesis regulated by eukaryotic initiation factors (eIFs) is a crucial step in controlling gene expression. eIF3a has been shown to regulate protein synthesis and cellular response to treatments by anticancer agents including cisplatin by regulating nucleotide excision repair. In this study, we tested the hypothesis that eIF3a regulates the synthesis of proteins important for the repair of double-strand DNA breaks induced by ionizing radiation (IR). We found that eIF3a upregulation sensitized cellular response to IR while its downregulation caused resistance to IR. eIF3a increases IR-induced DNA damages and decreases non-homologous end joining (NHEJ) activity by suppressing the synthesis of NHEJ repair proteins. Furthermore, analysis of existing patient database shows that eIF3a expression associates with better overall survival of breast, gastric, lung, and ovarian cancer patients. These findings together suggest that eIF3a plays an important role in cellular response to DNA-damaging treatments by regulating the synthesis of DNA repair proteins and, thus, eIIF3a likely contributes to the outcome of cancer patients treated with DNA-damaging strategies including IR.Item Harnessing Compensatory Pathways and Acquired Resistance in Treating Triple-Negative Breast Cancer(2024-08) Solzak, Jeffrey Peter; Schneider, Bryan P.; Radovich, Milan; Nephew, Kenneth P.; Palkowitz, Alan; Herbert, Brittney-SheaTriple-negative breast cancer (TNBC) is defined by the absence of estrogen-receptor (ER), progesterone-receptor (PR), and human epidermal growth factor receptor 2 (HER2) over-expression. While TNBC comprises a minority of breast cancer cases, about 15%, it results in a disproportionally higher rate of mortality compared to hormone positive breast cancers. Compared to individuals with ER and HER2 positive disease, individuals with TNBC will have a higher incidence of visceral metastasis, a higher likelihood of relapse within the first three years after chemotherapy and surgery, and a shorter overall survival after the onset of metastatic disease. Despite the recent approvals of targeted agents, including: immune checkpoint inhibition using pembrolizumab, the TROP2 antibody drug conjugate (ADC) sacituzumab govitecan, and PARP inhibitors for germline BRCA-mutated tumors, cytotoxic chemotherapy remains the mainstay treatment for metastatic TNBC. To identify novel targets that could potentially be harnessed for therapeutic combinations, we utilized a strategic method by analyzing compensatory genomic and transcriptomic responses to targeted therapy. We demonstrate this herein, by identifying a novel combination targeting the PI3K & Wnt pathways that elicited clinical efficacy in a Phase I clinical trial. We further build on our hypothesis by also studying real-world evidence to identify novel resistance mechanisms in TNBC patients treated with the TROP2 ADC Sacituzumab govitecan. Our data suggest that the comparison of compensatory mechanisms before and after treatment can potentially inform efficacious therapeutic decision-making. In summation, with these data presented, we provide opportunities for furthering the therapeutic landscape to give patients with this dreadful disease more options in the clinical setting.Item Herstory: female artists' resistance in The Awakening, Corregidora, and The Dew Breaker(2017-06) Schaefer, Mercedez L.; Thorington-Springer, Jennifer; Kubitschek, Missy Dehn; Kovacik, KarenFor women in patriarchal societies, life is stitched with silence and violence. This is especially true for women of color. In a world that has cast women as invisible and voiceless, to create from the margins is to demand to be seen and heard. Thus, women’s art has never had the privilege of being art for art’s sake and instead is necessarily involved in the work of articulating and (re)writing female experience. When women seek, through their work and art, to feel deeply and connect with other women, they tap into what Audre Lorde has famously termed “the power of the erotic.” Lorde suggests that to acknowledge and trust those deepest feelings within our bodies is a subversive power that spurs social change. In the following work, novels by Kate Chopin, Gayl Jones, and Edwidge Danticat are linked by their female characters who seek the erotic via their art of choice and, in doing so, resist disempowerment and explore the life-giving nature of female connection. Furthermore, because the authors themselves are engaged in rendering the female experience visible, the novels discussed actively converse with their respective waves of feminism and propel social activism and feminist discourse. Hence, this project provides both a close reading of The Awakening, Corregidora, and The Dew Breaker, and a broader contention on the role of women’s literature in social justice.Item Leaders as change executors: the impact of leader attitudes to change and change-specific support on followers(2022-01-11) Walk, MarleneOrganizational change research has long regarded leaders as instrumental for the successful implementation of change. Leaders, however, are not always initiating change but rather executing it. In those cases, leaders may hold negative attitudes with regards to the change content or even resist change implementation while also being less effective in supporting their followers. This study tests whether, and to what extent, leader attitudes alongside leader change-specific support impact follower resistance to change. Using survey data from school principals and teachers in the public education sector in Germany, findings from multilevel linear regression show that leader resistance is positively related to follower resistance while leader attitudes to change content are unrelated to follower resistance. Leader change-specific support strengthens the relationship between follower attitudes towards change content and their resistance to change. Thus, this study raises awareness of the negative impact leaders can have on their followers when they are executors rather than initiators of change.Item Mechanisms of Intrinsic Tumor Resistance to Immunotherapy(MDPI, 2018-05-02) Rieth, John; Subramanian, Subbaya; Surgery, School of MedicineAn increased understanding of the interactions between the immune system and tumors has opened the door to immunotherapy for cancer patients. Despite some success with checkpoint inhibitors including ipilimumab, pembrolizumab, and nivolumab, most cancer patients remain unresponsive to such immunotherapy, likely due to intrinsic tumor resistance. The mechanisms most likely involve reducing the quantity and/or quality of antitumor lymphocytes, which ultimately are driven by any number of developments: tumor mutations and adaptations, reduced neoantigen generation or expression, indoleamine 2,3-dioxygenase (IDO) overexpression, loss of phosphatase and tensin homologue (PTEN) expression, and overexpression of the Wnt–β-catenin pathway. Current work in immunotherapy continues to identify various tumor resistance mechanisms; future work is needed to develop adjuvant treatments that target those mechanisms, in order to improve the efficacy of immunotherapy and to expand its scope.Item A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells(Elsevier, 2019-03-12) Chefetz, Ilana; Grimley, Edward; Yang, Kun; Hong, Linda; Vinogradova, Ekaterina V.; Suciu, Radu; Kovalenko, Ilya; Karnak, David; Morgan, Cynthia A.; Chtcherbinine, Mikhail; Buchman, Cameron; Huddle, Brandt; Barraza, Scott; Morgan, Meredith; Bernstein, Kara A.; Yoon, Euisik; Lombard, David B.; Bild, Andrea; Mehta, Geeta; Romero, Iris; Chiang, Chun-Yi; Landen, Charles; Cravatt, Benjamin; Hurley, Thomas D.; Larsen, Scott D.; Buckanovich, Ronald J.; Department of Biochemistry and Molecular Biology, School of MedicineSummary Ovarian cancer is typified by the development of chemotherapy resistance. Chemotherapy resistance is associated with high aldehyde dehydrogenase (ALDH) enzymatic activity, increased cancer “stemness,” and expression of the stem cell marker CD133. As such, ALDH activity has been proposed as a therapeutic target. Although it remains controversial which of the 19 ALDH family members drive chemotherapy resistance, ALDH1A family members have been primarily linked with chemotherapy resistant and stemness. We identified two ALDH1A family selective inhibitors (ALDH1Ai). ALDH1Ai preferentially kills CD133+ ovarian cancer stem-like cells (CSCs). ALDH1Ai induce necroptotic CSC death, mediated, in part, by the induction of mitochondrial uncoupling proteins and reduction in oxidative phosphorylation. ALDH1Ai is highly synergistic with chemotherapy, reducing tumor initiation capacity and increasing tumor eradication in vivo. These studies link ALDH1A with necroptosis and confirm the family as a critical therapeutic target to overcome chemotherapy resistance and improve patient outcomes.Item Polished ‘Hoes’, Dancehall Queens, and Sexual Freaks: Voices From the Margins of Caribbean Literature(Office of the Vice Chancellor for Research, 2013-04-05) Springer, Jennifer ThoringtonPolished Hoes, Dance Hall Queens, and Sexual Freaks: Women’s Voices From the Margins is a book-length project that will examine multiply marginalized Caribbean women’s narratives of resistance as they challenge and transform the sexual politics of black communities. Scholarship in black studies, particularly in the Caribbean, tends to reward normative behavior and marginalizes women who do not conform to set standards, deeming them deviants and denying them black citizenship–access to national belonging–within their disparate nations. Those considered “deviants” and their troubled identities are not deemed worthy of national belonging. Analyzing Anglophone literature, film, news reports, texts written by underground groups, and popular culture, in English, Polished Hoes addresses two main questions: how do marginalized Caribbean women create radical identities and counter-subcultures as they resist oppression? And what new radical politics and communities evolve from these? Polished Hoes proposes a new black resistance theory grounded in the experiences of multiply marginalized women and their challenges to various forms of oppression.Item Quantification of spatial pharmacogene expression heterogeneity in breast tumors.(Wiley, 2022-07-30) Powell, Nicholas R.; Silvola, Rebecca M.; Howard, John S.; Badve, Sunil; Skaar, Todd C.; Ipe, JosephBACKGROUND: Chemotherapeutic drug concentrations vary across different regions of tumors and this is thought to be involved in development of chemotherapy resistance. Insufficient drug delivery to some regions of the tumor may be due to spatial differences in expression of genes involved in the disposition, transport, and detoxification of drugs (pharmacogenes). Therefore, in this study, we analyzed the spatial expression of 286 pharmacogenes in six breast cancer tissues using the recently developed Visium spatial transcriptomics platform to (1) determine if these pharmacogenes are expressed heterogeneously across tumor tissue and (2) to determine which pharmacogenes have the most spatial expression heterogeneity. METHODS AND RESULTS: The spatial transcriptomics technology sequences the transcriptome of 55 um diameter barcoded sections (spots) across a tissue sample. We analyzed spatial gene expression profiles of four biobank-sourced breast tumor samples in addition to two breast tumor sample datasets from 10× Genomics. We define heterogeneity as the interquartile range of read counts. Collectively, we identified 8887 spots in tumor regions, 3814 in stroma, 44 in lymphocytes, and 116 in normal regions based on pathologist annotation of the tissues. We showed statistically significant differences in expression of pharmacogenes in tumor regions compared to surrounding non-tumor regions. We also observed that the most heterogeneously expressed genes within tumor regions were involved in reactive oxygen species (ROS) handling and detoxification mechanisms. GPX4, GSTP1, MGST3, SOD1, CYP4Z1, CYB5R3, GSTK1, and NAT1 showed the most heterogeneous expression within tumor regions. CONCLUSIONS: The heterogeneous expression of these pharmacogenes may have important implications for cancer therapy due to their ability to impact drug distribution and efficacy throughout the tumor. Our results suggest that chemoresistance caused by expression of GPX4, GSTP1, MGST3, and SOD1 may be intrinsic, not acquired, since the heterogeneity is not specific to chemotherapy-treated samples or cell type. Additionally, we identified candidate chemoresistance pharmacogenes that can be further tested through focused follow-up studies.Item The Role of the Hedgehog Pathway in Chemoresistance of Gastrointestinal Cancers(MDPI, 2021) Liang, Yabing; Yang, Ling; Xie, Jingwu; Pediatrics, School of MedicineThe hedgehog pathway, which plays a significant role in embryonic development and stem cell regulation, is activated in gastrointestinal cancers. Chemotherapy is widely used in cancer treatment. However, chemoresistance becomes a substantial obstacle in cancer therapy. This review focuses on the recent advances in the hedgehog pathway’s roles in drug resistance of gastrointestinal cancers and the novel drugs and strategies targeting hedgehog signaling.